Efficient glucose metabolism is critical for maintaining cellular viability. Under normal nutrient and oxygen conditions, glucose is converted to pyruvate, which enters the mitochondria to be used for oxidative phosphorylation to produce ATP. Under hypoxia or nutrient stress, metabolism is switched to glycolysis, increasing lactate production and reducing mitochondrial respiration. This switch is critical to maintain cells during periods of starvation or hypoxia; furthermore, recent studies indicate that modulating this switch could be beneficial under a situation of chronic glucose imbalance, such as in patients with Type II diabetes. Little is known whether chromatin plays a role in carbohydrate flux. The yeast Sir2 protein is an NAD-dependent histone deacetylase that senses the metabolic status of the cell and functions as a chromatin silencer to promote lifespan and genomic stability. Seven mammalian Sir2 homologs have been found (SIRT1-7), but their functions remain to be fully elucidated. Recently, we discovered that the mammalian SIRT6 is a chromatin factor that influences glucose metabolism and DNA repair. In mice, SIRT6-deficiency provokes a profound and lethal hypoglycemia which culminates in accelerated death. At the cellular level, SIRT6 inactivation leads to increased cellular glucose uptake, higher lactate production and decreased mitochondrial activity. Preliminary results indicate that SIRT6 is a master modulator of glucose homeostasis, regulating expression of several key genes in these metabolic pathways. In this context, SIRT6 appears to function as a histone H3 lysine9 (H3K9) deacetylase to inhibit expression of glycolytic genes. The main goal of this proposal is to test specifically whether SIRT6 regulates nutrient stress in vivo, functioning as a chromatin modifier to modulate multiple genes involved in switching glucose metabolism away of glycolysis and towards mitochondrial respiration. PUBLIC HEALTH RELEVANCE: In order to survive under conditions of nutrient stress, cells trigger an adaptive response, re-routing glucose in order to produce enough energy to sustain their survival. The yeast protein Sir2 functions as a modulator of lifespan, sensing nutrient availability to adapt the cellular metabolic activity; while recent studies indicate that some of the mammalian homologs (termed sirtuins) play a role in stress resistance and metabolic homeostasis, their precise molecular functions remain to be fully elucidated. In this proposal, we will test the hypothesis that one of these homologs, SIRT6, modulates glucose metabolism as a critical regulator of multiple metabolic genes, and as such might influence ageing and age related diseases like diabetes and cancer.